Since, ancient times, the plant Artemisia annua (family: Asteraceae) has been used as a traditional Chinese herbal medicine known as Qinghao for treating fever and malaria. The effective constituent was isolated by the Chinese investigators in 1972 and shown to be the sesquiterpene lactone, named artemisinin or qinghaosu (Jing-Ming et al., 1979; Tu et <2/.,1981).The structure of artemisinin has now been confirmed by a variety of analytical methods. Because artemisinin posseses high plasmodicidal property, it holds considerable promise for the treatment of drug resistant malaria. Artemisinin is poorly soluble in water and oil but readily soluble in most aprotic solvents. This property coupled with its short half-life, as well as desire to improve more potent derivatives, led to the efforts for chemically modifying its structure and synthesizing new artemisinin derivatives. Thus, ether derivatives of artemisinin called arteethers were prepared from dihydroartemisinin by etherification with ethanol in the presence of Lewis acid.
Absolute stereochemistry of arteethers (a and 6 isomers) at C-12 was also determined and it is 2-3 times more potent than artemisinin. The compounds a and 8 arteethers were developed as an antimalarial drug in India by the Central Institute of Medicinal and Aromatic Plants (CIMAP) and Central Drug Research Institute (CDRI) after phase III clinical trials. The arteether is presently sold in the market under the trade name E-MAL (injection).
In our earlier invention, we found a novel selective property of the compound a-arteether, which is inhibitory against the gyr mutant strains of E.coli, but ineffective against wild type strains (U.S. Pat. No. 6,127,405). Further we also developed in a separate U.S. Pat. No. 6,423,741 a strategic and novel combinations of a arteether which can be used as advanced generation drug(s) to counter the resistance development itself while, having a potential to be used in treating infectious diseases particularly in those cases where drug resistant strains are known to appear very frequently.
The uniqueness and most useful feature is that, in a combination of a arteether and quinolone drugs and likewise, the spontaneous mutants arising resistant to quinolones or the derivatives will be killed by a arteether and at the same time any a arteether resistant strains become highly sensitive to nalidixic acid and hence eliminated by it through the combination approach. The new composition of compounds inhibits the resistance development due to mutation in the gyr A gene of bacteria, in which one component is a arteether and the other may be nalidixic acid or any of the fluoroquinolones (comprising of Ciprofloxacin, Norfloxacin, Levofloxacin, Sparfloxacin, Oxfloxacin and Lomefloxacin etc.) or compounds of similar nature against which the resistance may develop through a related process.
These above inventions were based on in vivo assays and do not indicate any insight into the genome for a arteether resistance mechanism based on which similar molecules can be structured/designed to target the DNA gyrase enzyme. Person skilled in the art may obtain clues from the present invention to design such molecules for a wide spectrum of microbes and hence the commercial importance of the invention.